Date: 11 Jul 1998 17:23:56
From: aidsnews@igc.org
Subject: AIDS Tratment News #298
AIDS TREATMENT NEWS Issue #298, July 10, 1998
phone 800-TREAT-1-2, or 415-255-0588
CONTENTS:
HIV-Specific Immune Responses Restored by HIV Immunogen Plus
Antiretroviral Suppression
Successful Treatment of "Buffalo Hump" with Growth Hormone
Geneva Conference Treatment Highlights
AIDS TREATMENT NEWS Internet Directory,
http://www.aidsnews.org
Women's Treatment Information and Advocacy: Position at
Project Inform
San Francisco, Oakland: Treatment Access and Information
Workshop, July 24, July 31, or August 14
SCIENTIFIC AMERICAN July Special Report on AIDS
***** HIV-Specific Immune Responses Restored by HIV Immunogen
Plus Antiretroviral Suppression
by John S. James
In what might be the most important treatment presentation at
the 12th World AIDS Conference (Geneva, June 28 - July 3),
New York University immunologist Fred Valentine, M.D.,
reported a striking return of HIV-specific immune responses
from a multicenter controlled trial of REMUNE(TM) (the Salk
HIV treatment vaccine, being tested by the Immune Response
Corporation of Carlsbad, California, and Agouron
Pharmaceuticals, Inc., of La Jolla, California; see AIDS
TREATMENT NEWS #297)--in a 43-patient clinical trial where
this potential treatment, called the HIV immunogen, was given
to patients whose viral load had been very well suppressed by
conventional antiretroviral treatment(1).
In almost all viral infections, control of the disease is
associated with a very strong "lymphoproliferative response"
(LPR)--the ability of certain immune-system cells in the
blood to recognize the virus and then grow rapidly, producing
many more such cells, which then mobilize other immune-system
cells against the virus. With HIV infection, however, it has
been known for years that the LPR to HIV is largely absent at
all stages of disease--except for a small minority of
patients, who do have a strong LPR against many antigens of
HIV. These patients are always long-term nonprogressors, able
to control the virus for many years and perhaps indefinitely,
without treatment.
Dr. Valentine presented preliminary results of a controlled,
double-blind clinical trial at eight medical centers, which
clearly showed that lymphoproliferative responses like those
of long-term nonprogressors can be induced by treatment in
patients who otherwise would not have them. These responses
were seen against an unrelated strain of HIV (not only
against the HIV immunogen itself). Whether these induced
responses are helpful like those which develop naturally
(earlier in infection) will not be known until some patients
stop their antiretrovirals and see if, or how rapidly, their
viral load returns.
Background
The lymphoproliferative response, measured by a complex
laboratory test, is a major indicator of how well a person's
immune system responds to a particular antigen (an antigen
usually consists of peptides, short sequences of proteins,
produced by a particular virus, bacterium, or other disease-
causing organism), which the body's cells had already learned
to recognize through previous exposure. The lack of this
response to HIV (in most patients, except for long-term
nonprogressors) has been a central mystery of this disease.
(Interestingly, chimpanzees--which can be infected with HIV
but seldom become ill--do have a strong LPR against HIV.)
The LPR is measured in the laboratory by culturing blood
cells from the patient in the presence of the antigen of
interest (here, HIV). Usually a small fraction of CD4+ T-
helper cells will be able to recognize the particular
antigen, and as a result they will begin to reproduce
rapidly. The amount of cell growth in the whole cell culture
can be measured by including tritium, a radioactive form of
hydrogen, in the growth medium, in a form that will be picked
up by and incorporated into growing cells. Later, technicians
separate the cells from the remaining growth medium, and then
they can easily measure how much radioactivity the cells
have.
The result of this test is given as a "stimulation index"--a
measure of how well that person's immune-system cells respond
to the antigen being tested. The stimulation index is the
ratio of how much radioactivity is present in cells from a
culture which included the antigen, vs. cells in a control
culture which was treated the same except that the antigen
was not added.
For example, the stimulation index of an HIV-negative person
who has been infected with CMV will often be in the range of
five to 50--meaning that when their cells were exposed to the
CMV antigen, a few recognized it and grew enough that the
culture as a whole took up five times to 50 times as much
tritium as the cell culture not exposed to the antigen. The
stimulation index can be as large as 100 or more; or on the
low end of the scale, a stimulation index of one means no
response (and an index of two could also mean no response,
due to errors in the testing). Measuring the LPR is labor
intensive and requires highly skilled technicians in order to
assure accuracy; as a result, this test of immune function
has remained a research method and not become part of
standard clinical practice.
In patients with HIV (except for long-term nonprogressors)
the LPR to HIV is very weak or not present at all. The LPR to
CMV and other opportunistic pathogens with which the patient
has been infected may be lost later in late-stage HIV
disease--but if the HIV is then suppressed with
antiretrovirals, the LPR to the opportunistic infections will
often come back. But the LPR to HIV does not occur by itself,
even when the virus has been fully suppressed and has
remained undetectable for years.
Why does the immune system of most patients fail to produce a
lymphoproliferative response to HIV? No one knows for sure,
but the dominant theory today is that HIV may kill off the
small fraction of T-helper cells which are genetically able
to recognize it--since these cells become activated during
primary infection and therefore are vulnerable to being
infected and destroyed by this virus.
The lack of HIV-specific LPR might explain why viral load
usually returns quickly if antiretroviral drugs are stopped.
But in the few long-term nonprogressors, the body somehow
gets the upper hand instead, HIV-specific responses are
preserved, and the virus remains controlled without
treatment.
An excellent review of this area by Dr. Valentine and others
appeared just before the Geneva conference in a supplement to
the June issue of AIDS RESEARCH AND HUMAN RETROVIRUSES(2).
This article referred to the study which Dr. Valentine
presented in Geneva (described below); however, the data was
blinded when that publication went to press, meaning that the
authors did not know what patients had received the real HIV
immunogen and which had received a placebo. There was an
indication that the treatment was working, however:
"Although the study is still blinded, approximately one half
of the subjects have developed stimulation indices to the gag
protein of between 10 and 400... These stimulation indices
and those obtained by immunization with envelope vaccines
often are as large as those seen in long-term immunological
nonprogressors who develop proliferative responses as a
consequence of their initial encounter with the virus."
[Note: The gag protein is a "core" protein of HIV. It tends
to be more constant from strain to strain than the "envelope"
proteins found on the surface of the virus.]
The Geneva Report
In a 10-minute "late breaker" session, Dr. Valentine gave a
preliminary report of a 32-week clinical trial conducted at
eight research centers; this trial had been completed, but
only the first 20 weeks of data had been analyzed and were
available for the presentation. Forty three patients were all
given antiretroviral therapy (indinavir plus AZT plus 3TC).
Four weeks later, they were vaccinated with either the REMUNE
HIV immunogen, or a control vaccination. The active or
control immunization was repeated every three months.
The purpose of this study was to see if the
lymphoproliferative response could be induced by immunization
when a patient's viral load was well suppressed by
antiretroviral drugs; previous data had suggested that this
might be possible. Other measurements included viral load
(using an ultrasensitive test with a lower limit of 40
copies), CD4 counts, and the level of the chemokine MIP-1-
beta.
The REMUNE HIV immunogen--a vaccine-type treatment for
persons already infected with HIV, designed by the late Dr.
Jonas Salk and currently in a large phase III trial, is made
from whole killed HIV from which the gp 120 envelope protein
has been removed. It also contains an adjuvant (IFA, or
incomplete Freund's adjuvant); an adjuvant is used to make a
vaccine work better. The control vaccine used in this trial
consisted of the adjuvant alone.
According to a July 3 press release from New York University
Medical Center, the 43 patients had a median CD4 count of 493
and a median viral load of 8,159 copies before they began the
study.
The patients who received the HIV immunogen consistently
developed strong lymphoproliferative responses like those of
long-term nonprogressors; some of the volunteers who received
the immunogen had stimulation indices in the hundreds. Those
who received the control vaccination (adjuvant only, without
the killed HIV) had very low stimulation indices, usually
around three for envelope proteins and slightly higher for
gag. Dr. Valentine also noted data from long-term followup of
one of the Merck trials; patients who had been on the same
antiretroviral regimen and had their virus undetectable for
almost three years (but who had not received any HIV
immunization) had no spontaneous recovery of their
lymphoproliferative response.
The LPR was tested by using different antigens--not only from
the HIV immunogen itself, but also a recombinant p24, and
most importantly, a whole virus from clade B--a strain of HIV
very different from the one used to make the immunogen.
(Clade B is the form of HIV which is common in North America.
But Dr. Salk developed the immunogen using an early HIV
isolate from a woman in Zaire. This virus later was found to
be a natural recombinant, consisting of a clade A envelope
and a clade G gag protein. This cross-clade reactivity of the
immunogen (to the clade B virus) suggests that if this
treatment turns out to be useful, it could be applied to
different HIV strains in different parts of the world.
The immune response to a clade different from that of the
antigen which induced it is unusual--but not especially
surprising in this case, however, since this virus targets
the gag protein, which tends to be relatively similar among
different strains of HIV (the envelope differs much more, but
this part of the virus is stripped off when the immunogen is
made). The lymphoproliferative response recognizes peptides,
which are short fragments of proteins--and the peptides from
different viruses are often the same.
Comment
This very important study leaves many questions unanswered.
The most urgent is whether the patients who had
lymphoproliferative responses induced in this way will
benefit from it and perhaps become long-term nonprogressors.
While it seems logical that the answer is yes, it is also
possible that LPR is only a consequence or marker of a good
immune response which controls the virus by some other
mechanism; it might not be the cause of the viral control by
long-term nonprogressors.
Many scientists did not expect this treatment to work, since
these patients had already been exposed to plenty of HIV
antigens due to viral replication. A major question now is
why the additional exposure to antigens through the vaccine
was so much more effective.
What surprises us is how well the study worked--since it can
take months or years for naive cells to recover in an adult
after immunosuppression. If the cells able to recognize HIV
had indeed been wiped out, as the predominant theory
suggests, could the lymphoproliferative responses have come
back so strongly in only 16 weeks (from the four-week point
of first immunization, to the 20-week point which contributed
the last data available for presentation in Geneva)? If,
however, the cells had not been destroyed but had been turned
off or suppressed in some way, then it would be important to
learn how the HAART (highly active antiretroviral treatment)
plus immunogen reversed such an effect. Perhaps a more
specific treatment could produce the same result.
The volunteers in this trial were relatively early in HIV
disease progression, but well past the stage of primary
infection. No one knows how well the approach would work on
persons with more advanced illness. It is often best to avoid
the more difficult cases when first establishing a proof of
principle--and then improve the treatment and extend it to
more patients.
Since this study was presented in one of two simultaneous
late breaker sessions at the very end of the conference,
there was little time for discussion among attendees before
people went home. Part of the data (from the patients at the
New York University site alone) had been reported by Dr.
Valentine the day before, during a satellite session
organized by the Immune Response Corporation; about 400
people showed up for this 6:30 a.m. meeting.
Other Studies
A number of laboratory and animal studies relevant to
restoring HIV-specific immunity were also presented at the
12th World AIDS Conference; we were not able to review them
before going to press. Also, other human trials which may
restore these responses are either ongoing, or now being
organized.
References
1. Valentine FT, DeGruttola V, Kaplan M, and others. Effects
of HAART compared to HAART plus an inactivated HIV immunogen
on lymphocyte proliferative responses (LPR) to HIV antigens.
12th World AIDS Conference, Geneva, June 28 - July 3, 1998
[abstract # 31227 (late breaker session, #LB 9)].
2. Valentine FT, Paolino A, Saito A, and Holzman RS.
Lymphocyte-proliferative responses to HIV antigens as a
potential measure of immunological reconstitution in HIV
disease. AIDS RESEARCH AND HUMAN RETROVIRUSES June 1998;
volume 14, supplement 2, pages S-161 to S-166.
***** Successful Treatment of "Buffalo Hump" with Growth
Hormone
by John S. James
A poster at the 12th World AIDS Conference reported
successful treatment of body fat redistribution in five
patients(1). All showed improvement, from 25% to total
resolution, usually with just a few weeks or months of the
treatment; there was also improvement in truncal obesity in
at least four of the patients. However, the patients'
elevated cholesterol and triglyceride levels did not improve
significantly. And there were suspected side effects of the
therapy, including hyperglycemia in two cases, elevation of
pancreatic enzymes in one, and carpal tunnel syndrome which
led to discontinuation of treatment in another.
The dose used was 5 to 6 mg per day of Serostim(TM), injected
subcutaneously.
This report was not from a study, but from experience in two
physicians' practices. The treatment was given primarily for
wasting, in the arms and legs--especially for the earliest
patients, since it was not known that growth hormone would
help correct the abnormal body fat redistribution.
Recently we have heard anecdotally of similar cases of
successful treatment of lipid redistribution with human
growth hormone. This presentation in Geneva may be the first
public report of successful treatment, other than surgery,
for the body shape changes which seem to be associated with
protease inhibitor treatment in some patients.
References
1. Torres, RA and Unger KW. Treatment of dorsocervical fat
pads (buffalo hump) and truncal obesity with Serostim(TM)
(recombinant human growth hormone) in patients with AIDS
maintained on HAART. 12th World AIDS Conference, Geneva, June
28 - July 3, 1998 [abstract # 32164]. Note: An updated and
extended abstract was distributed at the conference, and is
the one reviewed above.
***** Geneva Conference Treatment Highlights
by John S. James
About 12,000 people attended the 12th World AIDS Conference
(Geneva, Switzerland, June 28 - July 3), the major
international conference which takes place every two years.
Unlike the previous meeting (Vancouver, July 7-12, 1996),
where the big news was protease inhibitors, Geneva did not
have one major story but was characterized by solid
scientific advances--most of them good news. We are now in a
period of incremental more than revolutionary treatment
developments--although some of the reports in Geneva could be
revolutionary if they are confirmed.
Perhaps the most important single change in atmosphere at
this conference is that immunology is at last being taken
more seriously than before. Of course it has always been
known that the immune system is central to this disease, but
it has been easier to find clear targets for treatment
development against the HIV virus--and easier to identify
indicators of antiretroviral activity (since clearly less
virus is better than more) than to know which immune
responses are beneficial. As a result, virology has dominated
AIDS medical research, leaving AIDS immunology underfunded;
the great majority of immunologists in the U.S. and the world
today have never done any work in AIDS. Now there is
widespread consensus that this disconnect between immunology
and AIDS research must end.
We left Geneva with more optimism than much of the mainstream
press, which noted the lack of major treatment advances such
as the protease inhibitors at Vancouver, some setbacks in
treatments and vaccines, and the conclusion of many experts
that in fighting the AIDS epidemic, the focus must still be
on prevention, which is known to work but often held back by
politics. This difference in outlook is not because either
view is wrong, but because we are reporting different news.
AIDS TREATMENT NEWS is written primarily for persons who know
they have HIV and who have at least some access to modern
medical care (unfortunately the large majority of people in
the world do not). There are many promising developments
likely to result in important new treatment options during
the next several months or years. And most of the bad news
was already known, and has been widely reported in AIDS
TREATMENT NEWS and elsewhere.
Certainly we agree on the importance of prevention; no one
expects the epidemic to be stopped by finding and treating
everybody, and no proven safe and effective vaccine is
available today. But even though prevention is far more cost-
effective than treatment in saving lives overall, this is no
reason to give up on anybody. People need hope if they are to
mobilize for effective policies; millions of lives may be
saved by low-cost treatments; and research focusing on far
less costly antiretrovirals can benefit everybody, even those
with no financial constraints on their care.
Some of the treatment highlights of the Geneva conference--
which we plan to cover in separate articles--are:
* Restoration of patients' HIV-specific immune responses (in
this issue);
* New antiretroviral combinations now supported by data from
major clinical trials;
* More interest in hydroxyurea in antiretroviral
combinations;
* New information on combining approved drugs, such as
indinavir and ritonavir;
* A report of successful growth-hormone treatment of body-
shape changes which may be caused by protease inhibitors in
some patients (in this issue);
* New results on nerve growth factor for treating peripheral
neuropathy;
* Reduction of mother-infant HIV transmission to under one
percent;
* Concerns on the safety of combination antiretroviral
treatment during pregnancy;
* Progress in diagnostics, including an experimental test for
immune function, and one for viral load inside cells.
We will also look at what is being done on the conference
theme of "bridging the gap"--providing treatment for the 90
percent of people with HIV who do not have access today.
***** AIDS TREATMENT NEWS Internet Directory,
http://www.aidsnews.org
by Tadd Tobias
AIDS TREATMENT NEWS has rewritten its World Wide Web
directory site to coincide with our poster presentation at
the 12th World AIDS Conference in Geneva ("Internet AIDS
Information--Providing Quality Referrals," abstract #34218).
We developed this site to refer users to some of the Internet
AIDS treatment information we consider most reliable and
useful, and also to organize important "favorites"
("bookmarks") for convenient access by ourselves and others.
We chose a simple design with text only, to avoid delay and
software incompatibilities for users throughout the world.
We link to major treatment sites, official treatment
guidelines, news media stories, official conference sites,
independent conference reports, conference and meeting
calendars, advocacy and service organizations, medical
reference books, medical journals, AIDS drug interaction
guides, clinical trials information, AIDSLINE searches, "ask
an expert" sites, pharmaceutical company sites, buyers' clubs
for alternative/complementary therapies, and information on
access to care, among other categories. To avoid repeating
the work of others, we generally link to some of the most
useful lists which are already being maintained elsewhere.
Our official Web address is http://www.aidsnews.org. However,
the 'www.' is optional for this site. And with most modern
browsers, you only need to type 'aidsnews.org' (without the
single quotes) to reach our Internet directory.
***** Women's Treatment Information and Advocacy: Position at
Project Inform
Project Inform, located in San Francisco, is hiring an
Information and Advocacy Associate Coordinator, "to
coordinate and develop Project Inform's advocacy efforts and
treatment education materials on women-specific treatment
issues (Project WISE) and treatments for a number of
opportunistic infections." The projected hiring date is late
July. Interested persons should send a resume, letter of
interest, and samples of their writing to: IAA Search,
Project Inform, 205 13th St. #2001, San Francisco, CA 94103.
The person hired will write treatment information for Project
Inform publications, coordinate and participate in advocacy
efforts for research relevant to women living with HIV,
develop and implement strategies to improve access to
promising treatments, and speak on behalf of the organization
to community groups and others.
Job requirements include knowledge of HIV-disease
pathogenesis and treatment, knowledge of treatment issues of
concern to women, written, telephone, and verbal
communication skills, and computer experience.
***** San Francisco, Oakland: Treatment Access and
Information Workshop, July 24, July 31, or August 14
A free, one-afternoon workshop for case managers, counselors,
social workers, HIV service providers, and treatment
advocates will provide training in how to help clients gain
access to experimental or expensive treatments, and to find
HIV information and resources on the Internet and elsewhere.
This workshop, sponsored by the Community Consortium (an
organization of HIV physicians in the San Francisco area)
will be given in Oakland (Friday July 24, noon to 3:30 p.m.,
at the Center for AIDS Services, 5720 Shattuck Avenue at 57th
St.), and in San Francisco (Friday July 31, and also Friday
August 14, noon to 3:30 p.m., at the University of California
San Francisco Mission Center Building, 1855 Folsom Street at
15th.)
"We will give you an update on clinical issues that are
relevant to your clients, especially regarding side effects
and drug interactions with illegal or recreational drugs.
Second, we will teach you how to get your client access to
care; we'll show you how to link clients to clinical
research, drug assistance programs, and physician referral
programs. Finally, we will teach you how to keep yourself--
and your clients--educated about HIV treatment issues in the
future."
Although there is no fee, space is limited and
preregistration is requested. To register, fax your name,
agency, address, phone number, and the date you are
interested in attending to 415-476-6948, or call the
Community Consortium at 415-502-0657.
***** SCIENTIFIC AMERICAN July Special Report on AIDS
The July issue of SCIENTIFIC AMERICAN, now on the newsstands,
includes an excellent 10-article special report on AIDS,
written by leading experts in treatment, prevention,
epidemiology, vaccines, and other topics. Most of our readers
already have this information, but may find the issue useful
for friends, colleagues, or others who have not been involved
with AIDS and want current background on the epidemic.
***** AIDS TREATMENT NEWS
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email: aidsnews@aidsnews.org
Editor and Publisher: John S. James
Associate Editor: Tadd T. Tobias
Reader Services: Tom Fontaine and Denny Smith
Operations Manager: Danalan Richard Copeland
Statement of Purpose:
AIDS TREATMENT NEWS reports on experimental and
standard treatments, especially those available now. We
interview physicians, scientists, other health
professionals, and persons with AIDS or HIV; we also
collect information from meetings and conferences,
medical journals, and computer databases. Long-term
survivors have usually tried many different treatments,
and found combinations which work for them. AIDS
Treatment News does not recommend particular
therapies, but seeks to increase the options available.
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ISSN # 1052-4207
Copyright 1998 by John S. James. Permission granted for
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--
AIDS Treatment News
P.O. Box 411256
San Francisco, CA 94141
phone 415-255-0588 or 800-TREAT-1-2; fax 415-255-4659
email aidsnews@aidsnews.org